Although acute pain in response to injury is an important mechanism for reducing the extent of harm to an individual, the nervous system can undergo an adaptive change that results in pain that is perceived well beyond the time after the injury is healed (chronic pain) (Costigan et al., 2009). This chronic pain can be generated by a stimulus that is normally innocuous (allodynia), or the response to a noxious stimulus can be greatly exaggerated (hyperalgesia). Chronic pain is estimated to affect at least 100 million adults in the United States and can negatively affect quality of life (Institute of Medicine, 2011). The pharmacologic treatment of neuropathic (due to nerve injury) or other chronic pain relies heavily on the use of opiates or their derivatives (Reuben et al., 2015). These drugs have many adverse effects, including tolerance/hyperalgesia, which results in dose escalation, and the development of opiate addiction (Chou et al., 2015). Additional side effects of high dose, chronic administration of opiates include constipation, sleep-disordered breathing, fractures, hypothalamic-pituitary-adrenal dysregulation, and overdose, as well as effects on the cardiovascular and immune systems (Baldini et al., 2012). Other drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, muscle relaxants and antidepressants, as well as drugs targeting voltage-sensitive calcium channels (gabapentin and pregabalin) are used to treat chronic pain, but these treatments provide limited relief (Lunn et al., 2014; Moore et al., 2014; Schreiber et al., 2015; Smith et al., 2012; Sofat et al., 2017; Lozada, et al., 2008). In addition, chronic administration of high doses of NSAIDs, the next most popular drugs, after opioids, for treatment of chronic pain, is associated with a plethora of side effects, including stomach problems (such as bleeding, ulcer, and stomach upset), renal failure, high blood pressure or cardiac problems, fluid retention, rashes, or other allergic reactions (Marcum and Hanlon 2010). A third category of drugs to treat chronic pain are the more recently introduced blockers of the 5-HT and NE reuptake systems (Smith et al., 2012; Sofat et al., 2017). 5-HT/NE reuptake inhibitors also present a series of side effects including nausea, G.I. disturbances, fatigue but difficulty sleeping. More dangerous are the effects of rapidly stopping the use of these drugs if they are not relieving the chronic pain. These “withdrawal” effects include extreme mood swings, agitation, aggression, nightmares, confusion and electric shock-like sensations in the head and other parts of the body (Fava et al., 2018; Carvalho et al., 2016). In all cases, be it with opiates/opioids, NSAIDs or 5-HT/NE reuptake inhibitors, the escalation of dose for therapeutic success against chronic pain results in the emergence of severe side effects and more severe withdrawal signs if the use of the medication is stopped abruptly.
The majority of chronic pain sufferers, whose pain is not controlled by other classes of drugs, continue to use prescribed opiates/opioids for prolonged periods and at high doses. Because of growing concerns about the significant increase in the use of opiates to treat chronic pain, and the accompanying problems of overdose, misuse and diversion, labeled the “opioid crisis”, recommendations have been made to limit prescribed opioids to the lowest effective dose, and for the shortest effective duration, and importantly to develop new non-opioid medications based on scientific information about the etiology of chronic pain (Volkow and McLellan 2016; Taneja et al., 2017; Kirkpatrick et al., 2016).
Numerous attempts have been made to generate new and better pain medications by focusing on targets that are known to be involved in chronic pain (Yekkirala, et al., 2017; Worley 2017). Target selection is a key feature of chronic pain drug development efforts, and most programs have used the approach of targeting a single target/site, such as a receptor, which has been the approach of choice of the pharmaceutical industry for many years (Ramsay et al., 2018). However, targeting a single molecular entity to control a complex physiological system has resulted in agents with limited efficacy (Bozic et al., 2013). More recently, perceptions have changed, in part due to the design of effective multi-target drugs for treatment of schizophrenia, viral infections, asthma, cardiovascular disease, neurodegenerative disease and cancer (Ramsay et al., 2018). Such drugs produce partial inhibition of more than one target within a network, rather than total inhibition of a single target (Zimmerman et al., 2007; Millan, 2014; Talevi, 2015).
With regard to pain, one can focus on the systems that conduct sensory information from peripheral receptors, and those that transduce information within and between sensory neurons. One of the most investigated molecular mechanisms leading to chronic neuropathic pain syndromes is an upregulation of the activity of peripheral voltage-sensitive sodium channels (VSNaCs) (Wood et al., 2004; Lai, et al., 2004; Black et al., 2004; Coggeshall et al., 2004; Dib-Hajj et al., 2007). The tetrodotoxin-sensitive Nav1.7 channel is located along the projections and cell bodies of the slowly conducting nociceptive neurons, and its role in both acute and chronic pain has been clearly demonstrated by genetic manipulation in animals and by naturally-occurring genetic mutations in humans (Black et al., 2004; Wang et al., 2011; Lawrence, 2012). The Nav1.7 channel has been particularly linked to pain associated with inflammation, and its upregulation contributes to the increased generation and conduction of action potentials in chronic pain syndromes (Eijkelkamp et al., 2012). In addition, the activity of the Nav1.7 channel can amplify generator potentials and promote the activation of other sensory neuron VSNaCs including the tetrodotoxin-resistant Nav1.8 channel (Dib-Hajj et al., 2007; Choi & Waxman, 2011). The Nav1.8 channel has been linked to development of both inflammatory and neuropathic pain conditions. Overall, the upregulation of the activity of the Nav1.7 and Nav1.8 channels in peripheral sensory neurons constitutes a common component of induction and maintenance of chronic pain syndromes (Wang et al., 2011; Theile & Cummins, 2011; Laedermann et al., 2015).
The role of the excitatory amino acid, glutamate, in the physiology of normal pain sensing and transmission of chronic pain phenomena is also well established (Davies & Lodge, 1987; Dickenson & Sullivan, 1987; Childers & Baudy, 2007). Sensory neuron activation or damage produces increased release of glutamate from both peripheral and central neurons, and the released glutamate can act on nearby glutamate (NMDA) receptors, to contribute to peripheral sensitization (Fernandez-Montoya et al., 2017; Jang et al., 2004). The interaction of glutamate with NMDA receptors in the dorsal root ganglia (DRG) is also involved in amplification of sensory signals (Ferrari et al., 2014; Rozanski et al., 2013). NMDA receptors are therefore involved in both the initiation and amplification of a pain sensation and its transmission into the CNS. Upregulation of NMDA receptors is seen both in peripheral neurons and spinal cord after sensory nerve damage, and this upregulation is thought to contribute to chronic neuropathic pain (Petrenko et al., 2003). In particular, the quantity of the GluN2B (NR2B) subunit-containing NMDA receptors plays the most important role in development and maintenance of chronic pain syndromes (Karlsson et al., 2002; Iwata et al., 2007; Gaunitz et al., 2002; Wilson et al., 2005).
Based on this discussion, a medication that can simultaneously inhibit Nav1.7 and Nav1.8 channel activity, as well as inhibit the activity of NMDA receptors (particularly those that contain the GluN2B subunit), can be of benefit both in preventing the development of chronic pain by inhibiting receptor/channel upregulation, and in reducing pain even after the development of a chronic pain syndrome. Such a medication would not have to act in the central nervous system, but could prevent peripheral sensitization that leads to the development central sensitization and chronic pain, and/or dampen the initiation and transmission of chronic pain signals to the brain.